Many chronic inflammatory diseases, including periodontal infections, are biofilm-based pathologies mediated by commensal microbiota persisting within complex host-associated microbial communities. Determining the environmental cues that direct the physiological state (commensal versus pathogenic state) of oral anaerobes, is fundamental to development of therapeutic strategies for periodontal diseases. Recent studies indicate that the pathogenic potential of the anaerobic bacterium P. gingivalis is not solely dependent on its ability to colonize and proliferate; its physiological stte and its associations within the microbial consortium are fundamental to development of pathology. The central hypothesis for the studies proposed here is that the availability of L-arginine is a key signal that directs colonization and expression of virulence determinants in P. gingivalis. Our preliminary studies have shown that under L-arginine deplete conditions, P. gingivalis down regulates expression of fimbriae, inhibiting biofilm formation; and, in contrast, addition of L-arginine boosts expression of fimbriae and surface colonization. Thus, P. gingivalis adjusts its life style in response to changes in the availability of L-arginine. Moreover, this adjustment has a subsequent impact on its interactions with other bacteria and host cells. What remains unclear is why L-arginine is such an important amino acid to P. gingivalis and how changes in L-arginine availability affect its physiology. The goal of this application is to determine how P. gingivalis senses arginine availability and how it responds to this particular amino acid and to determine the effect of arginine on its interaction with human macrophages and oral epithelial cells. We posit that arginine is a critical resource that is crucial for immune regulation and P. gingivalis has evolved with the ability to sense and respond to this key amino acid, not just as a growth substrate, but as a fundamental strategy for persistence. The rationale for these studies is that identifying the signals that control colonization and the physiological state of oral pathogens will provide prime targets for the development of therapeutic strategies. Thus, the long-term objective is to determine if this mechanism of signaling can be targeted for treatment and prevention of biofilm-induced diseases in humans.